There have been known that NO (nitrogen monoxide) is generated in vivo when L-citrulline is formed by oxidation of the constitutional nitrogen atoms in the guanidino moiety of arginine through N-hydroxy-L-arginine intermediate. This reaction proceeds by action of NO synthase (hereinafter referred to as NOS) which acts as a catalyst.
There have been known several types of NOS, thus cNOS (constitutive NOS) which is constitutively existed naturally in the cells, and iNOS (inducible NOS) is synthesized inductively by stimulation of cytokaines or endotoxins [e.g., lipopolysaccharide (LPS)]. Examples of cNOS, includes endothelial cell NOS (eNOS) and nerve cell NOS (nNOS), and examples of iNOS includes macrophage NOS (mNOS).
Excessive amounts of NO and its metabolic products formed in vivo by the action of above-mentioned NOS (mainly, iNOS) induce several activities, such as lowering the blood pressure, activation of guanylate cyclase, acceleration of ribosylating adenosine diphosphate (ADP), deactivation of iron-containing enzymes, inhibition of synthesis of proteins and nucleic acids, inhibiting aggregation of platelet, inhibiting adhesion of neutrophil, etc., thus NO takes part in onset of various diseases.
For example, NO has an influence to disturb the native functions of the cells. Therefore, when a certain amount of NO is generated in the cells due to postponement of over-manifestation of iNOS, then it is understood that NO acts as a disturbance factor to the living body.
The disturbance factor is known to be regarded to various pathemas for example, septic shock, inflammations, reperfusion disturbance, arteriosclerosis, hypertension and myocarditis which may be occurred relating to the blood vessels and cardiac system; pneumonia and asthma which may be occurred relating to the lung and respiratory system; acute renal failure and glomerular philitis which may be occurred relating to the renal system; neurotoxicity, spasm, migraine, hyperesthesia which may be occurred relating to the brain and nervus system; mucosal disturbance, ulcerative colitis and diabetes mellitis which may be occurred relating to the digestive system; chronic rheumatic arthritis and the like which may be occurred relating to the immunological system.
Asthma is basically occurred due to spasmodic contraction of smooth muscle of the airway together with inflammation of the airway, deposition of viscous secreta inside of the airway, and edema of the airway mucosa.
There have been proposed several theories relating to pathogenesis of asthma, e.g., 1) mechanism based on allergy, 2) infections with microorganisms, 3) autonomic imbalance, 4) psychoneurotic cause, 5) .beta.-blocking theory, 6) predisposing cause, 7) over response of the airway, 8) a specific mechanism, etc., and among of these theories the mechanism based on allergy is considered as the most important cause.
In asthmatic patients, there are two types of symptoms, one of them is an immediate asthmatic response (IAR) in which the asthmatic attack is induced quickly after the exposure to an antigen, another of them is a late asthmatic response (LAR) in which the asthmatic attack is manifested slowly thus, several hours after the exposure to an antigen. At present, an agent for inhibiting LAR is particularly desired.
Currently, .beta.-stimulant drugs, steroidal anti-inflammatory drugs are mainly administered to asthmatic patients. However, there are reported that asthmatic patients are encountered in high risk to asthmatic death in case of administered .beta.-stimulant drug in high dosage. As to the mechanism of side-effects of .beta.-stimulant drug, the cardiac arrhythmia and drug tolerance are considered to be the highest possibility.
Additionally, steroidal anti-inflammatory drugs are indeed effective to cure asthmatic symptoms, while they bring serious systemic side-effects. Of cause, certain countermeasures are tried to reduce such side-effects caused by inhalation type of steroidal drugs. However, similar to oral administration type drugs, some dangers may be caused to osteoporosis and lowering of lung compliance by such inhalation type drugs. Thus, any drug being capable of replacing steroidal drugs, or any drug having the ability at least to reduce the dosage of the steroidal drugs are desired.
For the purpose to reduce dosage of steroidal drugs, there are reported that mild effects for reducing the dosage can be expected by using Methotrexate, a gold salt containing drug and cyclosporins. However, these drugs itself have severe side-effects which are different from the side-effects shown by the steroidal drugs. Thus, any drug without having these side-effects are desired.
On the other hand, although calcium antagonists may be used for reducing constriction of the airway, but they show much side-effects and are not practical. While by using PAF (platelet activating factor) antagonists, there was not reported any preferable results in curing asthmatic disease.
Under the circumstances, any drug being capable to substitute steroidal drugs or any drugs having similar effect to steroidal drugs without side-effect is desired. That is, any drug effective to patient who is suffering from the disease caused by tolerance to steroidal drug or vicious asthmatic disease such as asthma resistant to steroidal drug is desired.
It is known that amounts of NO and its derivatives in the exhalation of bronchial asthmatic patient is found to be increased.
Also, it is understood that NO is closely relates to the constriction of smooth muscle of the trachea together with inflammation of the airway, also relates to atopic dermatitis.
With respect to a pyrimidine derivative represented by the general formula (1) of the present invention, having inhibitory action against the effects of NO, the present inventors have made studies on anti-allergic activities, especially on anti-asthmatic effect and anti-atopic dermatitis effect performed thereby. As the result, the inventors have found the facts that, the pyrimidine derivative (1) of the present invention is a compound to be substituted for conventional steroidal drugs or a compound which is capable to reduce the dosage of conventional steroidal drugs, for this reason that the pyrimidine derivative (1) possesses activity for inhibiting the generation of NO, especially it performs an excellent effect for curing the late asthmatic response (LAR), also possesses an equivalent or higher performance in anti-asthmatic effect and anti-atopic dermatitis, as compared with the activity shown by conventional steroidal anti-inflammatory drug.
As to the NOS inhibitors to be used for curing the above-mentioned diseases, there are known, for example L-NMMA (N.sup.G -monomethyl-L-arginine), L-NA (N.sup.G -nitro-L-arginine), L-AME (L-arginine methyl ester), L-NAME (N.sup.G -nitro-L-arginine methyl ester) and the like.
However, administration of these NOS inhitors cannot good enough for cure the above-mentioned various diseases. Under such circumstances, novel compounds having excellent activities for inhibiting the formation of NO in vivo and in case of curing asthma, an agent to be able to substitute for steroidal drugs, or an agent having at least effect for saving the dosage of steroidal drugs is desired.
In JP-A-5-112571, WO 97/11946, WO 95/35298 and JP-A-6-312987, there are disclosed pyrimidine derivatives similar to the pyrimidine derivatives (1) of the present invention. However, there are not any disclosure relating to the activity for inhibiting the formation of NO performed by these pyrimidine derivatives known in these prior art.